Purpose:
Dock8, an atypical guanine nucleotide exchange factor (GEF) for Rho-family of small GTPases, has gained much attention since the discovery of Dock8 mutations in a combined immunodeficiency syndrome in humans. However, it is unknown whether Dock8 deficiency may be effective in inflammatory demyelinating disorders including optic neuritis. Therefore, we investigated roles of Dock8 and Dock10, a homologue of Dock8, in inflammatory demyelination.

Results:
T-cell numbers in spleen were significantly reduced in Dock8 KO mice, but not in Dock8 Tg and Dock10 KO mice. Dock8 deficiency absolutely protected the optic nerve and spinal cord from inflammatory demyelination indicating that Dock8 is required to elicit autoimmune T-cell responses. The disease incidence was nearly halved in Dock8 Tg mice, and diseased EAE mice showed markedly decreased clinical signs, in which recovery was observed at later timepoints. In addition, a similar amelioration of inflammatory demyelination was observed in Dock10 KO mice; this resulted from suppression of cytokine production, namely, MIP-1α and MCP-1, in glial innate immunity.

Conclusions:
Our findings suggest that manipulation of Dock8 and Dock10 signaling may serve as a novel therapeutic strategy against inflammatory demyelinating disorders.